Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases

Abstract Mutations in the human FAM111B gene are associated with a rare, hereditary multi‐systemic fibrosing disease, POIKTMP. To date, there are ten POIKTMP‐associated FAM111B gene mutations reported in thirty‐six patients from five families globally. To investigate the clinical significance of these mutations, we summarized individual cases by clinical features and position of the reported FAM111B gene mutations as those within and outside the putative protease domain (MWPPD and MOPPD respectively). MWPPD cases had more clinical manifestations than MOPPD (25 versus 18). Although the most common clinical features of poikiloderma, alopecia and hypohidrosis overall occurred in 94%, 86% and 75% of all cases with no significant differences between the MOPPD and MWPPD group, less common features included life‐threatening (pulmonary fibrosis 47% vs. 13%; liver abnormalities specifically cirrhosis 26% vs. 7%) and physically disabling conditions (myopathy 53% vs. 20%; tendon contracture 55% vs. 7%) were more common in MWPPD cases. Similarly, the only 2 cases of POIKTMP with fatal pancreatic cancers were both only in the MWPPD group. This review thus suggests that mutations within the putative protease domain of the FAM111B protein are associated with a broader range of clinical features and may predict increased POIKTMP severity and a poorer prognosis.

and mediastinal. 2,3 Furthermore, these POIKTMP cases presented variable phenotypes, some displaying very few clinical features and others displaying up to twenty-five. We report in this review a total of twenty-six of these clinical manifestations in thirty-six cases of POIKTMP (Table 1, Table S1).
The associated or causal missense mutations of POIKTMP were identified in the Family with sequence similarity 111-member B (FAM111B) gene by whole-exome sequencing. 3 Ten POIKTMPassociated mutations are reported in five families and individuals, totalling thirty-six cases globally (Table S1). Moreover, three non-POIKTMP-associated FAM111B gene mutations are reported in two cases of colorectal cancers and a case of progressive osseous heteroplasia (POH). 8,9 These mutations/cases do not form part of the ten mutations and thirty-six cases evaluated in this review.
Although the physiological role of the FAM111B gene and gene mutations in POIKTMP are yet to be elucidated, recent studies have suggested that mutations may result in induced cytotoxicity resulting from the upregulation of a putative serine protease-like domain in the FAM111B protein 10 or the overexpression of the FAM111B gene product as seen in some adenocarcinomas. 11 Mutations of the Furthermore, a case report on POIKTMP hypothesized that the location of the mutation could contribute to the phenotypic variation and disease severity 7 ; however, this remains unconfirmed.

| ME THODS
From our summary of these clinical manifestations into twentysix groups, we observed that some features are widespread or unique to specific cases (Table 1). In all cases, the most common clinical characteristics (i.e. found in ≥40% of all cases and given the term

| Association of POIKTMP clinical manifestations and position of FAM111B gene mutations
Ten POIKTMP-associated mutations (nine missense and one inframe deletion) of the human FAM111B gene are reported to date (  Table 2 and Table S1) had similar clinical features and likely had identical mutations with family members who underwent genetic testing. 6 Furthermore, there was no information on the gene mutations in two individual cases (Cases 19, Table 2 and Table S1). 15,16 In all, we analysed the FAM111B gene mutations in thirty-four cases. Even though, 55% of these mutations resulted from a paternal and maternal inheritance, compared with the 42% of spurious (i.e. de novo) mutations, suggesting this syndrome may also result from a non-mendelian pattern of inheritance ( Table 2).

35,
The bioinformatic analysis of the amino acid sequence of the  (Figure 1 and Table 2). In these thirty-four POIKTMP cases, fifteen falls in the MOPPD group, while nineteen are in the MWPPD group (Table S4).    (Table 2).
In all, our analysis tends towards supporting the notion that patients with MWPPD in the FAM111B gene have a higher disease burden and poor disease prognosis than patients with MOPPD.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to declare.

AUTH O R CO NTR I B UTI O N S
All authors contributed equally to the drafting of this article. AA and NK conceptualized the review. AA and CR searched, reviewed and analysed the data generated from the case reports. AA wrote the first draft of the manuscript. AA and NK revised, edited and organized the manuscript's content.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

S U PP O RTI N G I N FO R M ATI O N
Additional supporting information may be found in the online version of the article at the publisher's website.